Trans-spinal direct current modulation systems

ABSTRACT

Improved neuromodulation control of neurological abnormalities associated with effector organs in vertebrate beings using direct current stimulation for modulating spinal cord excitability, having a peripheral-current supplying component for providing direct current peripheral nerve stimulation and a spinal-current supplying component providing direct current for spinal stimulation, and a controller managing such functions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims is a continuation of co-pending U.S. applicationSer. No. 14/579,829, filed Dec. 22, 2014, entitled: Trans-spinal DirectCurrent Stimulation Systems. Priority is also claimed upon U.S.Provisional Application Ser. No. 62/092,214, filed Dec. 15, 2014,entitled: Trans-spinal Direct Current Stimulation Systems, U.S.Provisional Application Ser. No. 61/925,423, filed Jan. 9, 2014,entitled: Method and Apparatus for Safe Regulation of Muscle Tone, andU.S. Provisional Application Ser. No. 61/919,806, filed Dec. 22, 2013,entitled: Method and Apparatus for Regulation of Muscle Tone. All of theforegoing are incorporated herein by reference in their entirety for allpurposes whatsoever.

FIELD

The present invention relates to method and apparatus for modulatingspinal cord excitability for regulation of effector organs, such asregulation of muscle tone and regulation of autonomic system functions.

BACKGROUND

The nervous system includes the Central Nervous System (CNS) and thePeripheral Nervous System (PNS), the latter including the SomaticNervous System (SNS) and Autonomic Nervous System (ANS). The CNSincludes the brain and the spinal cord. The spinal cord is the maincommunication route for signals between the body and the brain. The PNScarries signals outside the brain and spinal cord throughout the rest ofthe body, including carrying motor signals to muscles and carryingsending feedback to the brain, including touch and pain signals from theskin. The SNS and ANS overlap the CNS and PNS. There are 31 pairs ofspinal nerves arising from cervical (8), thoracic (12), lumbar (5),sacral (5) and coccygeal (1) segments. The spinal nerves contain bothsensory and motor fibers. Efferent nerves (as opposed to afferentnerves) are the nerves leading from the central nervous system to aneffector organ, and efferent neural outflow refers to neural signalsfrom the brain that are transmitted via spinal cord pathways to effectororgans.

The SNS is the part of the peripheral nervous system associated with thevoluntary control of movement via the skeletal muscles. The ANS consistsof two divisions, the sympathetic nervous system and the parasympatheticnervous system, and is responsible for regulating bodily functionsincluding heart rate, respiration, digestion, bladder tone, sexualresponse and other functions. Activation of the sympathetic nervoussystem results in preparation of the body for stressful or emergencysituations, while activation of the parasympathetic nervous systemresults in conservation and restoration and controls body processesduring normal situations. The autonomic nervous system includes bothsensory and motor neurons. Preganglionic neurons start in the CNS andproject to a ganglion in the body where they connect with postganglionicneurons that connect with a specific organ.

There are many disorders and dysfunctions associated with abnormalregulation of effector organs, which may be due to disturbances in anycomponent of the nervous system. These effector organs can be skeletalmuscles under voluntary control, smooth muscle under autonomic control,or visceral organs and glands. We have developed a novel approach tomodulating these systems using trans-spinal direct current stimulation(tsDCS).

Muscle tone abnormalities are associated with many neurologicalpathologies and can severely limit motor function and control. Muscletone depends on the level of excitability of spinal motoneurons andinterneurons. Muscle tone abnormalities can be due to either decreasedtone (hypotonus) or increased tone (hypertonus). Hypotonia is commonlyobserved, for example, in patients with cerebellar deficits andspinocerebellar lesions and in developmentally-delayed children,including those with Down's syndrome. Hypertonia is commonly observed,for example, in patients with cerebral palsy, stroke, spinal cord injury(SCI), brain injury, multiple sclerosis and numerous other neurologicaldisorders. Hypertonia includes spasticity and rigidity and ischaracterized by a velocity-dependent increase in tonic stretch reflexesand increased muscle activity during passive stretch. Spasticity canrange from mild to severe and can cause striking impairments infunctional movement. There is a long felt need for better ability tocontrol and regulate muscle tone. Spinal cord injury is one indicationwhere an increase in muscle tone is often seen.

Increases in reflex excitability following SCI may be caused by a numberof factors, including increased excitability of spinal motoneurons andchanges in interneuronal physiology and connectivity. In general,following SCI, increased excitation and reduced inhibition of themechanisms controlling motoneurons causes abnormal generation of force,resulting in spasticity. Pharmacological, surgical, and physicaltreatments to manage spasticity have at best short-term efficacy and areconfounded by side effects.

Beyond skeletal muscle disorders, there are numerous disorders relatedto dysfunction of either the sympathetic or parasympathetic system thathave been described. These ANS disorders are referred to asdysautonomias, and can be due to failure or disruption of either thesympathetic or parasympathetic divisions of the ANS. Specific suchdisorders include familial dysautonomia, autoimmune autonomicganglionopathy, congenital central hypoventilation syndrome, Holmes-Adiesyndrome, multiple system atrophy, Shy-Drager syndrome, neurallymediated syncope, orthostatic hypotension, postural tachycardiasyndrome, striatonigral degeneration and vasovagal syncope. No effectivetreatments currently exist for these dysautonomias. A novel approach toautonomic neuromodulation would not only open new treatment options forthese patients, but would enable the harnessing of the autonomic nervoussystem to modulate the activity of all the organ systems innervatedautonomically.

There remains a need for improved method and apparatus forneuromodulation and regulation of effector organs.

SUMMARY

In one or more embodiments, the method of these teachings includesapplying a source of electrical stimulation along a nerve that providesneural control of a target effector organ and applying a source ofdirect current to a spinal location associated with efferent neuraloutflow to the target effector organ.

A number of other embodiments including a number of methods of use arealso disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

The above illustrative and further embodiments are described below inconjunction with the following drawings, where specifically numberedcomponents are described and will be appreciated to be thus described inall figures of the disclosure:

FIGS. 1 and 2: Illustrate an embodiment of these teachings forregulating the median nerve for resolving a chronic fisted hand andfingers with high muscle tone.

FIG. 3: Charge-balancing electrode device.

FIG. 4: Shows major nerve associations/combinations for electrodeplacement in human subjects, in illustrative practices of theseteachings.

FIG. 5: Shows spinal-to-sciatic or sciatic-to-spinal treatment formuscles innervated by the sciatic nerve for either down or up-regulatingmuscle tone in the leg, depending upon signal polarity applied from thesource. The configuration shown in FIG. 11 with anodal spinal cathode isfor down-regulation.

FIG. 6: Shows a packaged muscle tone regulator system in a practice ofthese teachings.

FIGS. 7-8: Shows special electrodes fixed neural electrode sets withleads in practice of embodiments of these teachings.

FIG. 9: Block diagram of an illustrative embodiment of these teachings.

FIGS. 10A and B: Show a wearable tsDCS device of these teachings.

FIGS. 11 and 12: Show representations of the autonomic nervous systemand sites of intervention;

FIG. 13: Shows Neuromodulation strategy for modulating renal functionbased on increasing parasympathetic tone.

FIG. 14: Shows an illustrative embodiment for treating bladder muscletone abnormalities in a practice of these teachings providing astimulation device in a housing as a wearable muscle tone regulator fornon-invasive stimulations in practice of embodiments of these teachings,or as an implantable stimulator.

FIG. 15: Shows Neuromodulation strategy for modulating renal functionbased on decreasing sympathetic tone.

FIG. 16: Shows Neuromodulation strategy for modulating renal functionbased on increasing sympathetic tone.

FIG. 17: Shows Neuromodulation strategy for treating urinary retentionbased on increasing parasympathetic tone.

FIG. 18: Shows Neuromodulation strategy for treating urinary retentionbased on inhibiting somatic efferents.

FIG. 19: Shows Neuromodulation strategy for treating urinary retentionbased on stimulating sensory afferents.

FIG. 20: Shows Neuromodulation strategy for treating urinaryincontinence based on decreasing parasympathetic tone.

FIG. 21: Shows Neuromodulation strategy for treating urinaryincontinence based on stimulating somatic efferents.

FIG. 22: Shows Neuromodulation strategy for increasing GI peristalsisand secretions based on decreasing sympathetic tone. tsDCS shown only atL2 level but extends across all relevant spinal levels of effector organbeing targeted. Stimulation of post-ganglionic fibers shown only distalto hypogastric plexus, but alternatively includes fibers distal to theceliac ganglion and SMG.

FIG. 23: Shows Neuromodulation strategy for increasing GI peristalsisand secretions based on increasing parasympathetic tone.

FIG. 24: Shows Neuromodulation strategy for treating fecal incontinencebased on increasing sympathetic tone.

FIG. 25: Shows Neuromodulation strategy for treating fecal incontinencebased on decreasing parasympathetic tone.

FIG. 26: Shows Neuromodulation strategy for treating fecal incontinencebased on stimulating somatic efferents.

DETAILED DESCRIPTION

The description is not to be taken in a limiting sense, but is mademerely for the purpose of illustrating the general principles of theseteachings, since the scope of these teachings is best defined by theappended claims.

The above illustrative and further embodiments are described below inconjunction with the following drawings, where specifically numberedcomponents are described and will be appreciated to be thus described inall figures of the disclosure:

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise.

Definitions

The following definitions pertain to the present disclosure, with theunderstanding that such may be modified by context of use. For purposesof the teaching of the present teachings:

The term “nerves” may be referred to herein as including nerves,neurons, motor neurons and interneurons and the like, and are generallyreferred to herein as “nerves” or “neurons”;

The terms or concepts of nerve stimulation and neural stimulation areused liberally and interchangeably to describe applications of thestimulation of the teachings;

The terms neuromodulation, modulation, stimulation and regulation areused interchangeably as equivalents for purposes of this disclosure andindicate an effect imposed upon a target in practice of presentteachings;

The terms dysfunction, disorder, defect and abnormality are usedinterchangeably as equivalents for purposes of this disclosure andindicate the concept of medically recognized conditions suitable formedical intervention:

The term effector organ refers to a neurally-ennervated organ thatproduces an effect in response to nerve stimulation. Muscles areincluded within such definition for purposes of this disclosure. Theeffects of stimulation of the present teachings upon an effector organor muscle may be discussed interchangeably for purposes of inclusivediscussion of the present teachings.

The term “stimulation,” as used herein, refers to either excitation orinhibition of nerve fibers, also referred to as up regulation or downregulation.

The term “electrical stimulation,” as used here in refers to theproduction or introduction of current into spinal nerve, neuron, circuitor pathway, whether by applying a voltage or magnetically inducing acurrent.

Improved method and apparatus for neuromodulation and regulation ofeffector organs are disclosed herein below.

In one or more embodiments, the system of these teachings includes afirst stimulation component configured to provide stimulation of a nerveassociated with a target effector organ and a second stimulationcomponent configured to provide spinal direct current stimulationassociated with modulation of said target effector organ.

In one instance, an embodiment of the system of these teachings alsoincludes a controller component configured to simultaneously control therange of current supplied by the first and second stimulationcomponents.

In one instance, the first stimulation component includes a firstelectrical source with positive and negative terminals providingstimulation current to stimulation electrodes, including two electrodesdisposed for stimulation of a nerve associated with a target effectororgan; one electrode operatively connected to the positive terminal andanother electrode operatively connected to the negative terminal; eachone of the two electrodes being electrically insulated from the otherone of the two electrodes. In one embodiment, the two electrodes arelocated noninvasively and are skin-surface electrodes. In anotherembodiment the two electrodes are implanted electrodes. In one instance,the first electrical sources also implanted and the controller componentis operatively connected to the first electrical source by a wirelessconnection.

In one instance, the second stimulation component includes a secondelectrical source having a second positive terminal and a secondnegative terminal, a first electrode disposed to be placed at a spinalcord location and a second electrode disposed to be placed at a locationselected from another location at the spinal column or a location distalfrom the spine. One of the first and second electrodes is operativelyconnected to the second positive terminal and another one of the firstand second electrodes is operatively connected to the second negativeterminal.

In one embodiment, the first and second electrical sources are the samesource. In another embodiment, the first and second electrical sourcesand the control component are located in a wearable housing. In oneembodiment, the source is a DC source. It should be noted thatembodiments in which the first electrical source is a pulsed source,such as a pulsed DC source, are also within the scope of theseteachings. Although less frequently used, embodiments in which thesource is a pulsed AC source are also within the scope of theseteachings.

Many abnormalities and dysfunctions are associated with regulation ofeffector organs, which may be based on disturbances in the nervoussystem. Management of such abnormalities by regulation of effectororgans, including regulation of muscle tone abnormalities, is a seriousand sometimes insurmountable challenge. Embodiments of the presentteachings are directed to meeting the need for stimulation systemsutilizing improved neuromodulation for control of abnormalitiesassociated with effector organs in vertebrate beings.

Embodiments of the present teachings feature applications of directcurrent stimulation (DCS) at the spinal cord and in various embodimentincludes stimulation of an associated nerve. Such associated nerve mayinclude a nerve associated with a particular effector organ formodulating control thereof or may be a peripheral nerve associated witha muscle for modulating control thereof.

Trans-spinal direct current stimulation (tsDCS) modulates spinal nerves,neurons, circuits and pathways. Embodiments of the present teachings,include tsDCS paired with a second neural stimulation set apart from thelocation of tsDCS spinal stimulation, and in that sense separated fromor peripheral or distal to the location of spinal stimulation, and istherefore referred to herein as non-spinal or peripheral DCS (pDCS) foraffecting an associated body part. This second stimulation includesapplied-energy stimulation of a nerve associated with a target bodypart, such as a nerve to an effector organ, a peripheral nerve to atarget muscle, or other nerve of interest, for achieving a particularoutcome associated with the target body part. A target body part mayinclude any part of the body having an associated nerve whosestimulation can modulate an associated function. As such, referenceherein to the PNS and peripheral nerves will be understood as areference to a subset of the systems and nerves associated withapplication of pDCS stimulation according to the present teachings. Thusnerves outside of the PNS and peripheral or distal to the spinal cordare within the term pDCS.

In an embodiment of these present teachings, spinal stimulation isdelivered as non-varying (e.g., non-time varying) constant-currenttsDCS. In embodiments of these present teachings, the tsDCS and a pDCSstimulation are delivered as non-varying constant direct currentstimulations.

In embodiments of the present teachings, systems are configured forup-regulation and/or down-regulation of target effector organs forimproved activity. In an illustrative embodiment, the present teachingis configured to provide down-regulation of muscle tone to reducespasticity or up-regulation of muscle tone to reduce flaccidity.Embodiments of the present teachings for treating hypertonia andreducing muscle tone feature anodal tsDCS and cathodal pDCS, asgenerated by cooperation of the anode of a spinal direct currentstimulation circuit and the cathode of a peripheral nerve direct currentstimulation circuit of the present teachings (“spine-to-nerve”).Embodiments of the present teachings for treating hypotonia andincreasing muscle tone feature anodal pDCS and cathodal tsDCS, asgenerated by cooperation of the anode of a peripheral nerve directcurrent stimulation circuit and the cathode of a spinal direct currentstimulation circuit of present teachings (“nerve-to-spine).

In practices of the present teachings, we teach application of positiveand negative signals to define direct current electrical circuits forstimulation of a nerve associated with an effector organ having anabnormality associated therewith and for stimulation of a location onthe spinal cord, such as at nerves of a spinal enlargement location,which is neurally associated with that nerve and organ, thus defining aneural pathway of interest.

In practices of the present teachings, if a particular body part has aneurological abnormality, then an associated nerve may be stimulated toregulate activity of such body part. In one embodiment, a spinalstimulation circuit is established by placing a spinal stimulationelectrode at a spinal location adjacent to a selected spinal nervecommunicating via a connecting neural pathway with a nerve associatedwith regulation of said body part, and the spinal stimulation circuithaving a reference electrode placed anterior to the spine.

In one such embodiment, a neural stimulation circuit is also establishedat a peripheral (i.e., non-spinal) nerve associated with regulation ofthat body part, such nerve normally communicating via the connectingneural pathway to that selected spinal nerve. A pair of electrodes arelocated across a section of such peripheral nerve, a first electrodebeing proximal to the spine and a second electrode being relativelydistal to the spine relative to that neural pathway. In variousembodiments, this array of electrodes is provided as a charge-balancingelectrode device including a first electrode and second electrodearrayed as insulated electrodes on a flexible substrate and havingexposed electrode surfaces and configured to be placed or affixed acrossa section of the target nerve associated with the effector organ ofinterest for polarization of the nerve section. Thus the first andsecond electrodes are either anode or cathode and cooperate as oppositepoles of the neural stimulation circuit to deliver the pDCS non-spinal,peripheral direct current stimulation of the present teachings.

The spinal stimulation electrode and the spinal reference electrode areeither anode or cathode and cooperate as opposite poles of the spinalstimulation circuit. Interaction of a pair of proximal poles betweenthese two circuits, spinal and peripheral, as anode and cathode,establish a third resulting polarization circuit of these teachings tomodulate the level of excitability of spinal motoneurons andinterneurons as will address the neurological abnormality of interest,such as, for example, for regulation of muscle tone.

These stimulation circuits have directional current flow betweenpositive and negative poles, i.e., between defining electrodes. It isthe interaction between respective poles of these stimulation circuitsthat produces the desired polarizing current flow of the third circuit.

In practice of these teachings, a polarizing current flow of theresulting polarization circuit is defined between a respective anodesand cathodes of spinal stimulation circuits and neural stimulationcircuit, for polarizing neurons, motoneurons and interneurons, along theconnecting neural pathway between such spinal location and target nerve,e.g. a peripheral nerve. In embodiments of the present teachings, theresulting polarization circuit is defined by: (1) direct current flowingfrom spinal cord to nerve, spine-to-nerve, anode-to-cathode inhibitsspinal motor neurons and intemeurons, hence down-regulating the nerve ofinterest and reducing muscle tone at the muscle of interest; or (2)direct current flowing in the opposite direction from nerve to spinalcord, nerve-to-spine, cathode-to-anode, excites spinal motor neurons andinterneurons, hence up-regulating the nerve of interest and increasingmuscle tone at the muscle of interest. Current intensity is constrainedto be equal to or greater at the spinal stimulation circuit versus atthe neural stimulation circuit.

Practices of these teachings demonstrate marked effects of DCS onfunction of effector organs, including regulation of muscle tone. Muscletone abnormalities impact treatment of many neurological conditions andseverely limit recovery of motor control. Muscle tone depends on thelevel of excitability of spinal motoneurons and interneurons. In controlmice and mice with spinal cord injuries with spasticity,spinal-to-sciatic DCS reduced transit and steady stretch-induced nerveand muscle responses. Sciatic-to-spinal DCS caused opposite effects.These findings provide the first direct evidence that trans-spinal DCScan alter muscle tone and demonstrate that this approach can reduce bothhypotonia and hypertonia. We have found similar effects in humans.

We have shown that dorsal surface anodal stimulation of the spinal corddecreases spinal excitability, while cathodal stimulation increasesexcitability, and we have shown that trans-spinal direct currentstimulation (tsDCS) modulates spinal neuron excitability, and that tsDCSmodulates the excitability of primary afferent fibers via theirpresynaptic terminals. These findings of the presently disclosedteachings enable clinical trans-spinal DCS applications for treatingeffector organ and muscle disorders. In one practice of these teachings,disorders of maladaptive excitation-inhibition balance are treated,demonstrating substantial reduction in spasticity.

The present teachings have been demonstrated in mammals, including miceand humans. Significant to human therapeutic application, a six year oldmale child with chronic fisted hands, diagnosed with spastic cerebralpalsy, was treated in practice of these teachings. After 10 minutesstimulation in practice of the teachings on the right hand,exceptionally high muscle tone and spasticity was reduced and the fistedhand unfolded. The result has been persistent. In a second session,after 10 minutes stimulation in practice of these teachings on the lefthand, exceptionally high muscle tone and spasticity was reduced and thefisted hand also unfolded. The result also has been persistent.

Common muscle groups that can be treated in practice of these teachings,along with characterization of alternative treatments, are shown inattached Table 1. This is a sample of muscle groups and body parts thatcan be treated in practice of these teachings. Pharmacological treatmentoptions, side-effects and surgical options are shown in Tables 2, 3 and4.

Embodiments of the present teachings provide method and apparatus forcontrol and modulation of effector organ activity, such as modulation ofmuscle tone through dual applications of direct current stimulation:trans-spinal direct current stimulation tsDCS at the spinal cord coupledwith other direct current stimulation pDCS at a peripheral location andnerve associated with treatment of an abnormality. In practices of thepresently disclosed teachings, dual simultaneous DCS affects effectororgans by modulating spinal cord excitability, wherein these teachingsmodulates background activity level of the motoneuron pool to change thefiring threshold of the motoneurons.

The present teachings meets the long felt need for improved method andapparatus for enabling restoration of effector organ functions andregulation of muscle tone. In one aspect of the teachings, aneuromodulation system includes two sources of constant DCS forsimultaneous provision of stimulation applied independently to the spineand to nerve(s) associated with a target to be treated. We disclosemethod and apparatus for modulating of spinal cord excitability,including use of tsDCS modulation of spinal cord excitability coupledwith pDCS (the latter preferably featuring a segment of polarized nerveachieved with a charge-balancing electrode device of these teachings).In an embodiment of these teachings, simultaneous trans-spinal tsDCS andperipheral pDCS are provided for up or down regulation of variouseffector organ functions of interest.

EMBODIMENTS

The present work demonstrates effects of trans-spinal sciatic-to-spinalor spinal-to-sciatic direct current stimulation on physiological andpathological abnormalities in treatment of effector organs such as inregulation of muscle tone. Overall, these results show that DCS affectsmuscle tone by modulating spinal cord excitability and that simultaneousstimulation with the presently disclosed tsDCS combined with pDCSresolves muscle tone dysfunction with long term effect. This hassubstantial clinical value in treatment of a wide range of effectororgan disorders.

Embodiments of the present teachings utilize special circuits: The firstcircuit involves current flow between a skin surface electrodepositioned above the spinal cord and a reference electrode, the latterat an abdominal skin or other non-neural area, for delivery of tsDCS. Inpractice of these teachings, this current path fosters inhibition withan anodal spinal electrode and cathodal abdominal electrode orexcitation when these polarities are reversed and current flows in thereverse direction. Typically, and compared to the peripheral nervecurrent path, relatively higher current intensity is needed in thespinal-abdominal current path to have consistent effects on spinal motorneurons and interneurons. The need for higher current intensities at thespinal cord might be due to the larger conductive volume and relativelygreater distance between the spinal cord and the electrode. This circuitcan be used to deliver tsDCS without other stimulation. However, thesecond circuit supplies peripheral nerve direct current stimulation,pDCS, and in conjunction with tsDCS, long term effects in spinalneuromodulation is achieved.

In regard to treatment of muscle tone, we find and adapt resultsshowing: (1) local changes in the excitability of the distal nervesegment (e.g., sciatic) are not a factor in the action of trans-spinalDCS, however, (2) excitability changes in the proximal nerve segment(e.g., sciatic) are a critical factor in modulating DCS-induced muscletone changes. This is supported by the finding that application ofcurrent to only a nerve circuit (e.g., sciatic) or an abdominal circuithad no effect on muscle tone; simultaneous stimulation of both circuitsis required to change muscle tone in practice of these teachings.

The present results are the first demonstration of trans-spinalDCS-induced alterations in muscle tone, and they have great clinicalapplications. Trans-spinal DCS can be applied non-invasively to humansto treat or manage various muscle tone abnormalities. Moreover, tsDCScan be applied through implantable electrodes to manage severeconditions (e.g., dysfunctional bladder, dysfunctional anal sphincterand many others) using a benchtop, wearable or implantable stimulationsystem of these teachings. In addition, since spinal-to-sciatic DCS canincrease muscle tone, it has the potential to amplify muscle tone inconditions in which muscle tone is abnormally low (e.g., patients withcerebellar deficits, spinocerebellar lesions and indevelopmentally-delayed children, including those with Down's syndrome).

Further illustrative and preferred embodiments of these teachingsshowing tsDCS modulation of spinal cord excitability for muscle toneregulation, method and apparatus, for use in mammals, are providedbelow. Embodiments of these teachings enable treatment of mammals,especially humans, non-invasively or with use of an implant, to achievethe desired outcome of well-regulated effector organs and muscles. Inapplications, tsDCS+pDCS, spinal-to-nerve (positive to negative) ornerve-to-spinal (positive to negative), modulates spinal neuronexcitability and activity, down or up, as indicated, respectively.

The present teachings teach applications of trans-spinal DCS to affectmuscle tone by modulating spinal cord excitability and is applied intreatment of living beings, in both human and veterinary applications.Practices of the present teachings treat hypertonic or hypotonicconditions. In one illustrative practice of the present teachings, wetreat a spastic hand in patients having spastic cerebral palsy, bydown-regulation of the high muscle tone. In another practice, we treatweak muscles such as at lower limbs in patients with Down's syndrome, byup-regulation of muscle tone. These are examples by way of illustrationand not by way of limitation of the scope of these teachings.

FIGS. 1-2 show an embodiment of the present teachings providing aneffector organ regulating device 10 having a tsDCS-pDCS stimulationcircuit 11 for modulating spinal cord excitability. Circuit 11 is drivenby variable constant DC source S at inputs S1 and S2 (either internal tothe system or from external power source). Depending upon desireddirection of current flow, S1 and S2 are positive or negative. For amuscle tone down-regulating configuration of device 10, source S1 andthe spinal electrode 20 are positive, and source S2 and the proximaldistal nerve electrode 26 are negative. For an up-regulatingconfiguration of the device, source S is switched accordingly to applyDC with S1 negative and S2 positive, and thus the spinal electrode wouldbe cathodal and the proximal nerve electrode anodal. This switching canbe accomplished internal or external to device 10, although it ispreferred that all electrode sources are switched internally andsimultaneously so as to avoid unwanted combinations of polarities beingpresented to the electrodes.

It will be appreciated that, in various embodiments of this disclosure,the modulation circuit is shown having nomenclature a1, c1, a2, c2,indicating specific anodal and cathodal branches as would apply to thedown-regulating embodiment of anodal spinal and cathodal nerve. Morespecifically, in FIG. 1 this would be correct where input S1 is positiveand S2 is negative, however this is a matter of illustration and not amatter of limitation of the disclosure and reversal of S1 and S2 willconvert the same circuit to anodal nerve and cathodal spinal for muscletone up-regulation. Safe operating condition is spinal current I1 equalsor is greater than neural current I2.

Regulating device 10 will either down-regulate (inhibit) or up-regulate(excite) to modulate activity associated with a target effector organ.The present method and apparatus can be applied to down-regulate muscletone to relieve a fisted spastic hand and fingers or can be similarlyapplied to other muscles of interest. Direction of current flowdetermines function. Anodal spine to cathodal nerve stimulation willdown-regulate muscle tone so as to reduce spasticity and rigidity, whileanodal nerve to cathodal spine stimulation will up-regulate muscle toneso as to reverse flaccidity.

FIGS. 1 and 2 illustrate an example of regulation of the median nervefor resolving a chronic fisted hand and fingers with high muscle tone.Stimulation circuit 11 has a spinal branch 12 for supplyingsub-threshold stimulation to the spinal cord 14 at a first current levelI1, measured at ammeter 15, and has a neural branch 16 for supplying tothe nerve of interest (e.g., median nerve) sub-threshold stimulation ata second current level I2, measured at ammeter 17. When setting up fortreatment, the current I2 is brought up to measurable EMG and thenreduced to subthreshold (no apparent nerve activity). Meanwhile, spinalDC is always subthreshold because of its low intensity (about 2 to 4 mA)when applied on the surface of the skin. However, in the case ofimplantable spinal electrodes, these intensities might produce activityand in this case adjustment would be made to reduce currents until noapparent nerve activity is observed.

Spinal branch 12 includes spinal electrode 20 positioned at the spinalcord 14. In some embodiments, the location of electrode 20 on the spinalcord is at the cervical enlargement for upper limb muscles to be treatedand at the lumbar enlargement for lower limb muscles to be treated, aswill be appreciated by a person skilled in the art. For treatment ofhand and fingers, it is at the cervical enlargement E-1 behind electrode20 in FIG. 1. A reference electrode 22 (return electrode) is positionedon an anterior location, such as the abdomen, as shown, or a bonylocation or the like.

In practices of the present teachings, the nerve stimulation ischarge-balanced, wherein the nerve is stimulated using an electrodearray presented as charge-balancing electrode device 27 for the neuralelectrodes. This charge-balancing electrode array of device 27 has twoinsulated and oppositely charged electrodes 26, 28 which are mated infixed relation on an insulating layer 29. This fixed device 27 is placedwith the two opposite charged electrodes across the nerve segment 30,with minimized separation for the purpose of reducing the risk ofdamaging effects of monopolar stimulation along a greater length of thenerve as may have a long term polarizing effect.

Care is taken to achieve sub-threshold current density upon thestimulated nerve area. As well, as earlier described, the rationale forcreating and placing our charge-balancing electrode device 27 upon thetarget nerve is to reduce the potential for damaging effects ofmonopolar stimulation at the nerve. The charge-balancing electrodedevice 27 as described above works at the neural location to assure safeapplication of neural stimulation, maintaining fixed and close relationbetween fixed electrodes 26, 28. This shortened length of nerve that isenervated bounded by the fixed cathodal and anodal electrodes willobviate and minimize risk of any such damaging effects.

Neural branch 16 includes a charge-balancing circuit 24 comprisingvariable resistor VR1 defining a first leg L1 resistively connectedbetween input S2 and proximal electrode 26 of charge-balancing electrodedevice 27, and also a variable resistor VR2 defining a second leg L2resistively connected between input S1 and distal electrode 28 of theelectrode device 27. Electrodes 26, 28 of charge-balancing electrodedevice 27 are mounted in fixed relationship on over local nerve segment30′ (FIG. 3) of nerve 30, in this example median nerve 30 on arm 31shown in FIG. 2.

It will now be appreciated that in embodiments of the present teachings,a first pair of electrodes 20, 22 are part of a first stimulationcircuit 12 to apply trans-spinal direct current stimulation (tsDCS) tothe spine 14 and a second pair of electrodes 26, 28 are part of a secondstimulation circuit 16, the latter to apply stimulation to nerve 30associated with the target body part. In turn, these two circuits definea resulting polarization circuit 33 defined between respectiveelectrodes 20 and 26, shown in FIG. 1 as between an anodal electrode 20of the spinal circuit 12 and a cathodal electrode 26 of the neuralcircuit 16. The resulting polarization circuit 33 stimulates the spineand achieves a desired regulation of excitability of effected spinalmotoneurons and intemeurons that enables the desired outcome ofregulation of muscle tone.

The active spinal electrode 20 is preferably located at a spinalenlargement 1, 2 FIG. 10. The spinal enlargement is selected as beingassociated with a nerve that is associated with control of the body partof interest. A reference spinal electrode (second pole) is affixed at ananterior location such as at the abdomen. The tsDCS is applied betweenthese two electrodes/poles to electrically polarize the zone of tissuebetween the two electrodes. In this embodiment, the second polar circuit16 is located at and energizes peripheral nerve 30 associated withcontrol of the target body part (arm/hand). The proximal and distalelectrodes 26, 28 (i.e., two poles) of this circuit 16 are arrayed overthe target nerve 30 to define a short stimulation section 30′ of thatnerve between these two electrodes (poles) this limits the reach ofpolarization at this nerve 30.

Such second stimulation circuit can be applied to locations in manyparts of the body and the character of stimulation energy will beselected accordingly. In the embodiment of FIGS. 1-2, peripheral nervedirect current stimulation (pDCS) is applied between electrodes 26, 28to create a zone of polarization across nerve section 30′

Down regulation and up regulation of muscle tone are guided by thedirection of the interaction between these adjacent electrodes of thespinal and neural circuits 12, 16 that define the polarization circuit33. For down-regulation, the spinal electrode 20 is positive (“anodal”)and proximal peripheral nerve electrode 26 must be negative(“cathodal”). This defines the needed spine-to-nerve polarizationcircuit 33 (polarizing current flow path) between these two energizedelectrodes of the two polar circuits 12, 16 for down-regulation. Forup-regulation, the proximal nerve electrode 26 is positive (“anodal”)and spinal electrode must be negative (“cathodal”). This defines theneeded nerve-to-spine polarization circuit 33 (polarizing current flowpath) between these two energized electrodes of the two polar circuitsfor up-regulation.

FIG. 3 shows another embodiment of charge-balancing electrode device 27having electrode conductive pads 114, 116 mounted on non-conductivesubstrate 112, and as applied in contact with nerve N. Electrodes 114,116 are attached to substrate 112 in inset metal pockets P1, P2 whichare in contact with electrical leads 118, 120 (or alternativelyelectrodes 114, 116 are attached in direct contact with ends of theleads without using the metal pockets P1, P2). The electrodes arepreferably sponge electrodes with conductive gel. In one embodiment, thesubstrate 112 is 8 cm×6 cm and the sponge pads 114, 116 are 2.5 cmsquare affixed in the metal pockets P1, P2 on insulating substrate 112,wherein the sponge pads are separated by 2 cm as affixed.

Returning to FIGS. 1-2, neural proximal and distal electrodes 26, 28always have opposed polarities from each other, and the polarity ofspinal electrode 20 is always opposite polarity to its own referenceelectrode 22 and to the polarity of the proximal neural electrode 26.Reversal of polarity of the adjustable Source S and thus at S1/S2reverses the polarity of the entire circuit 11, thus maintaining thisoppositional relationship. When the spinal electrode 20 is positive (andits reference electrode 22 is negative), the neural proximal electrode26 is negative and the distal electrode 28 is positive; and vice versawhen polarities of S1/S2 are reversed.

As shown in FIG. 1, the present teachings provides a regulating device10 having tsDCS-pDCS stimulator 11 circuits that form the desiredresulting polarization circuit 33 and that can be used either fordown-regulating or up-regulating effector organ activity includingmuscle tone. In one practice of these teachings, an isolated powersupply having two separate 18 volt battery sets supply isolated constantcurrent to the two circuits 12, 16 from the adjustable DC source S, atS1 and S2.

Referring to FIG. 1, when S1 is positive and S2 is negative, in adown-regulation embodiment, the circuit inhibits spinal motoneurons andinterneurons and reduces muscle tone at the muscles associated with thestimulated nerve. When the signals at S1 and S2 are reversed, i.e.,where S2 is anode and S1 cathode, the device operates to excite spinalmotoneurons and interneurons and increases activity at the effectororgans, e.g., muscle(s) of interest associated with the chosen nervebeing stimulated.

In some experiments, current in circuit 11 was applied in the relationof spinal current I1 to distal neural current I2 sometimes at around160:1 in mice and around 2:1 to 3:1 in humans. But in all subjects theratio can range depending upon body size, type, age, fat level, etc., aswell as the specific neurological deficit, or whether the nerve ofinterest is less responsive or not easily stimulated from the surface,and this will impact needed levels of current stimulation. Even so, thepresent teaching is easily setup and operated in veterinary and humanpractices even where these ratios may vary widely patient to patient.

The electrodes of regulation device 10 are attached to the subject andthe spinal circuit is properly set. An electromyography (EMG) device isconnected to monitor increased stimulation at the muscle of interestassociated with the nerve as stimulated by the current flow. As will beappreciated by a person skilled in the art, in the present example ofthe median nerve stimulation, the EMG was attached across the thumb tomeasure action potential at the abductor pollicis brevis muscle (on thepalm side of the hand). The pre-treatment clenched first and EMGattachment at the thumb is indicated in FIG. 1 and FIG. 2.Post-treatment, spasticity was reduced as the hand and thumb were nowrelaxed and extendable, and no longer clenched.

In an illustrative embodiment, the following method was followed fortreatment of spastic hand in a seated patient. The method featuredanodal spinal electrode and cathodal proximal electrode at median nerveto decrease muscle tone of a rigid hand and fingers. This is shown byway of illustration and not as limitation of the spirit and scope of thepresent teachings.

Spinal electrode placement: the anode electrode placed over the cervicalregion to cover C6 to the upper edge of T1. (Before placing eachelectrode, the skin should be thoroughly cleansed with alcohol.)

Abdominal electrode: cathode electrode placed over anterior abdominalskin or other location that is not a major neural location.

Median nerve electrode placement: a charge-balancing electrode devicewith two separate electrodes: the distal electrode (toward the hand) asanode; the proximal electrode (toward the head/cervical enlargement) ascathode. Preferably the double electrode set is placed over the frontaspect of the wrist joint across and over a section of the median nerve.

Electromyography electrode placement: bipolar electrodes record EMG fromthumb muscles, placed over the abductor pollicis brevis (APB).

Tuning the stimulator: The stimulator output is brought to threshold andreduced to produce no EMG activity from the nerve/muscle. Inillustrative practice of these teachings, about 4 mA at thespinal-abdominal circuit and about 2-3.5 mA at the median nerve circuitachieves desired results in a human. However, in small subjects thebranch values may converge, such as 2-2.5 mA at both the nerve andspinal column. In the case of such a subject, typically a child, theadjustable power source S would be adjusted to bring the spinal circuitto about 2-2.5 mA and the variable resistor VR1-VR2 would be adjusted,thus bringing the nerve electrode set also to about 2-2.5 mA. In thiscase the current ratio I1:I2 would be as close as 1:1.

Typical treatment duration: The duration is for 20 min. (Atbeginning/end of treatment ramping up/down is recommended for comfort.)

End of treatment: Turn the stimulator off (after ramping down to zeroinput). Inspect the skin under the electrodes for any skin changes.

In illustrative practices of these teachings, current at the spinal cordis first adjusted typically 2-4 mA on average, depending on age and bodytype/size, and access to nerve, etc., as would be appreciated by aperson skilled in the art. Generally, larger and stronger patientsrequire higher current level, and the spinal cord accepts a much higherdose versus the current at the more sensitive target nerve. However, ifthe nerve is buried or accessed through much tissue—possibly scarred orfatty—a higher stimulation level of the nerve may be required. In someexamples, there is low or no divergence of the spinal and nerve values,such as, for example, for an infant 2.5 mA at both spine and at nervecan be used. This low end regimen shows caution for the pediatricapplication and yet still achieves excellent modulatory results. Spinalcurrent may be reduced to reduce artifact at spinal electrode.Preferably electrodes are sponge-type and are applied with conductivegel.

Placement of Electrodes:

In embodiments of these teachings, for treating upper limb conditions,peripheral stimulation is at the level of the median nerve, ulnar nerve,radial nerve, brachial plexus, or smaller branches thereof, and fortreating lower limb conditions, peripheral stimulation is at the levelof the femoral nerve, sciatic nerve, peroneal nerve or smaller branchesthereof. As such, tsDCS devices are applicable to the treatment ofdisorders and dysfunctions of effector organs, including treatment ofmuscle tone impairments in patients with cerebral palsy, Parkinson'sdisease, stroke, traumatic brain injury, spinal cord injury, restlessleg syndrome, spastic paraplegia, cerebellar lesions, developmentaldisorders such as Down's syndrome, specific genetic diseases with muscletone impairment, and many other disorders affecting control of skeletalmuscle.

Application of the present trans-spinal direct current stimulation inhumans applies to treatment of many abnormalities. Anodal spinal tocathodal proximal nerve treatment is used for high muscle tonetreatment, for example: spasticity and rigidity from various sources,including after stroke; spasticity after spinal cord injury; spasticityand rigidity in cerebral palsy; rigidity in Parkinson's patients;spasticity after traumatic brain injury; dystonia. Anodal nerve tocathodal spinal treatment is used for low muscle tone and flaccidity,such as due to genetic disorders (e.g. Down's syndrome) or due todisease, or cerebellar and other traumas including those caused bysurgical interventions; among other cases.

Electrode placement depends upon location of the muscles of interest andthen upon identifying the associated nerve to be stimulated. Major nerveassociations (i.e., cervical enlargement 1, lumbar enlargement 2,brachial plexus 3, ulnar nerve 4, median nerve 5, femoral nerve 6,sciatic nerve 7 and peronial nerve 8) are shown in FIG. 4 for preferredelectrode placement in human subjects for down-regulating muscle tone.For down regulation, cervical or lumbar spinal electrodes are biasedpositive and the electrodes of the charge-balancing electrode device atthe nerve of interest are presented negative (proximal)/positive(distal).

Practice of these teachings includes selectively applying peripheralstimulation to the muscles listed below associated with spinalstimulation to provide the indicated result with reduced muscle tone andreduced spasticity in the following combinations:

a) spinal stimulation at cervical enlargement with peripheralstimulation at: brachial plexus to reduce muscle tone of the whole arm;ulnar nerve to reduce muscle tone of the arm muscles associated withulnar; median nerve to reduce muscle tone of hand and fingers; and

b) spinal stimulation at lumbar enlargement with peripheral stimulationat: femoral nerve to reduce muscle tone of knee extensors; sciatic nerveto reduce muscle tone of knee flexors and all muscle of the leg andfoot; and peroneal nerve to reduce muscle tone in the foot.

In another practice of these teachings, peripheral stimulation isapplied to the listed nerves associated with spinal stimulation with theindicated result of reduced muscle tone and reduced spasticity in thefollowing combinations:

a) anodal spinal polar stimulation at cervical spinal enlargement withcathodal peripheral nerve polar stimulation as treatment for indicatedhigh muscle tone and/or spasticity, at: brachial plexus to reduce muscletone of the whole arm; ulnar nerve to reduce muscle tone of the armmuscles associated with ulnar; median nerve to reduce muscle tone ofhand and fingers; and

b) anodal spinal polar stimulation at lumbar spinal enlargement withcathodal peripheral nerve polar stimulation as treatment for indicatedhigh muscle tone and/or spasticity; at femoral nerve to reduce muscletone of knee extensors; sciatic nerve to reduce muscle tone of kneeflexors and all muscle of the leg and foot; and peroneal nerve to reducemuscle tone in the foot; and

In another practice of these teachings, peripheral stimulation isapplied to the listed nerves associated with spinal stimulation with theindicated result of increased muscle tone and reduced flaccidity in thefollowing combinations:

cathodal spinal polar stimulation with anodal peripheral nerve polarstimulation as treatment for indicated low muscle tone, such as due togenetic disorders including Down's Syndrome, or due to disease, orcerebellar and other traumas including those caused by surgicalinterventions.

In FIG. 1, the spinal branch 12 biases spinal electrodes 20, 22 and thenerve branch 16 biases the nerve set of electrodes of charge-balancingelectrode array of device 27 in their complementary arrangements toachieve the desired current flow from anodal spine to cathodal nerve(muscle tone reducing) or from anodal nerve to cathodal spine (muscletone increasing). FIG. 5 shows spinal-to-sciatic or sciatic-to-spinaltreatment for muscles innervated by the sciatic nerve for either down orup-regulating muscle tone in the leg, depending upon signal polarityapplied from the source. The configuration shown in FIG. 5 with anodalspinal electrode is for down-regulation.

Referring to embodiments of FIGS. 6-9, a packaged regulator system 50includes a stimulator system and may be wearable, implantable, orstationary. Referring to FIGS. 6-9, in an exemplary system 50incorporating the stimulation system 10 and muscle tone stimulatorcircuit 11 as earlier described, has an external spinal circuit 12*formed by coupling spinal electrodes 20, 22 via wires 72, 76 to malejack 70 having pins 74, 77 connecting to pins 56,58 at mating femalereceptacle 54 on the system 50 housing, and which then is connected tothe earlier described spinal branch 12.

An external neural circuit 16* is established by coupling neuralelectrodes 26 and 28 of charge-balancing electrode device 27 via wires84, 86 to male jack 82 having pins 87, 89 for mating with receiver pins62, 64 at mating female receptacle 60 on the system 50 housing, andwhich then is connected to the earlier described neural branch 16.

In one embodiment, to assure correct signals are delivered to thecorrect electrodes, spinal jack 70 preferably includes a detent feature80 which must be accommodated by a cooperating detent feature 60 so asto enable mating of jack 70 and receptacle 54 in only one position toassure correct circuit connection. This arrangement assures that spinalelectrode 20 will always be coupled via wire 72 and jack 70 to pin 56 ofreceptacle 54 and reference electrode 22 will always be coupled via wire76 and jack 70 to pin 58 of receptacle 54. Furthermore, neural jack 82preferably includes a detent feature 88 which must be accommodated by acooperating detent feature 68 so as to enable specific mating of jack 82and receptacle 60 in only one orientation to assure correct circuitconnection for the charge-balancing electrode device 27. Thisarrangement assures that to assure correct signals are delivered to thecorrect electrodes and lessens the opportunity for human error inoperation of the system.

In one practice of these teachings, of FIG. 1, electrode 20 is a spongeelectrode and is color-coded such as with a blue marking (“B”) andcorrespondingly electrode 26 of charge-balancing electrode device 27 isof opposite polarity and is color-coded with a marking (“B”). Referenceelectrode 22 and distal electrode 28 are black. The spinal electrodes20, 22 are attached via jack 70 to system 50 and polarities are set fordown-regulation or up-regulation, respectively, by user interaction withcontroller 90 and touch display 92. Controller 90 then assures thatcharge-balancing electrode device 27, attached via jack 82 to system 50,presents the blue-coded electrode 26 at opposite polarity to the otherpolarity of the blue-coded spinal electrode 20. This then assures thatthe resulting polarization circuit 33 is properly formed.

The user applies the spinal electrode 20 to the spine as earlierdescribed. The user notes the blue-tagging and is reminded that thecharge-balancing electrode device 27 must be placed over the nerve ofinterest with the blue-coded electrode 26 oriented proximal to thespinal electrode 20 and electrode 28 oriented distal to the spinalelectrode 20. This prevents mistaken affixation of the charge-balancingelectrode device 27, and prevents the wrong electrode 28 being placedwhere the correct electrode 26 should be placed. This error wouldpresent the wrong polarity electrode to resulting polarization circuit33 and would make it ineffective.

Accordingly, the trained administrator always affixes the blue-codedspinal electrode 20 at the spine at the desired location and black-codedreference electrode 22 on a non-nerve location, as earlier discussed,and affixes the charge-balancing electrode device 27, preferably at anangle, e.g., at 90 degrees, across the nerve of interest (e.g., nerve30, FIG. 1), to define a short length of nerve segment 30′ to bestimulated, such that the oppositely-biased blue-coded electrode 26 ofcharge balancing electrode device 27 will be proximal to the blue-codedspinal electrode 20 and the black-coded reference electrode 28 ofcharge-balancing electrode device 27 will be distal to spinal electrode20, all with appropriate polarities fixed. Signal levels are againadjusted as earlier discussed.

Thus the trained administrator enters data at input 92 and controller 90of circuit 10 in system 50 which fixes spinal and neural electrodepolarities and signal levels according to body type and whethertreatment is for down or up-regulation of muscle tone. Blue spinalelectrode 20 is positive for down-regulation (or negative forup-regulation) and is paired with proximal blue-coded electrode 26 whichis oppositely negative (or positive) biased, while black referenceelectrode 22 is negative (or positive) and distal black electrode 28 ispositive (or negative), respectively.

In a further embodiment, a regulation system 100 of these teachingsshown in FIG. 9 includes the above electrodes and jacks, formed asspinal connection device 12* and neural connection device 16*, formating with receptacles 54, 60, of the included system 50, respectively.The system 100 includes DC power as part of or as supplied at DC source94 which is controlled by controller circuit 90 for supplying anddriving circuit 11 and for biasing electrodes 20, 22, 26, 28 viaconnection devices 12* and 16*. (FIG. 6 shows an external power sourcebut either internal or external power source can be used for portable orworkstation installation within practice of these teachings.Rechargeable batteries would be adequate.) User control interface isprovided at touch screen and display 92. Power is adjusted at variableresistor 51 and VR1-VR2 resistive set 52 according to indications atammeters 15/17.

It will be appreciated that the present teachings teach benchtop,wearable and implantable stimulation systems utilizing trans-spinaldirect current stimulation for control of effector organs. Embodimentsof these teachings enable regulation of effector organs and in oneembodiment control of muscle tone. This may be achieved with a medicaldevice with two sets of electrodes that are attached to the patient toprovide spinal stimulation and peripheral stimulation, and may bepresented as a benchtop stimulation system. In embodiments of theseteachings utilizing implantable electrodes, wearable or implantablestimulation devices may be employed. For certain applications,administration of tsDCS therapy for disorders at effector organs will besufficient if done between 1-5 times a week for a number of sessions onan outpatient basis. Indeed, we have seen beneficial results after asingle treatment in a child with cerebral palsy who had clenched fiststhat had never been able to open spontaneously until treatment with anembodiment of the present teachings enable resolution of his hypertonia.

For some patients, treatment on such a schedule will be insufficient.Constant application of tsDCS, or application for several hours orsessions per day, for practical beneficial effects may be indicated forsome. This can be assisted by enabling mobile delivery of such therapy.For such applications of tsDCS, embodiments of the present teachings arepresented as a wearable on-skin device or implantable device as shown inFIGS. 4 and 13. Such devices are compact versions of these teachings. Inone embodiment, the device footprint is shrunk to the approximatediameter of a silver dollar, and is attached to the skin surface of thespine with adhesive mounting, implanted magnets, or other methodologies.Pre-programming of microprocessor with memory 91 (FIG. 9) provides thecapability to accommodate such long-term treatment, with adequateinternal monitoring.

A tsDCS stimulation device delivers either anodal or cathodal directcurrent stimulation to the desired location on the spine, and in onepractice with the tsDCS device here taught, device 120. FIG. 10, servesas the dorsal electrode 122 and the reference electrode 124 is placed onthe skin surface of either the neck, abdomen, or other level dependingon the spinal level of stimulation, neck attachment shown in FIG. 10. Anelectrode lead 126 runs along the skin from the wearable tsDCS device tothe ventral skin-surface electrode 124. The wearable tsDCS device 120comes in different sizes and form factors depending on whether it isbeing used with adults or children, and depending on the spinal locationit is being used for. The wearable tsDCS device can be rechargeable, andremoved at night for charging and comfort of sleep.

The wearable tsDCS device attaches to the skin surface of the spine ateither the cervical, thoracic, lumbar or sacral levels depending on theeffector organ to be stimulated. In certain embodiments, there is a pairof electrode leads for peripheral nerve stimulation coming off thewearable tsDCS device. Peripheral nerve stimulation can be done throughskin-surface electrodes, subcutaneous electrodes, or implantedelectrodes.

The autonomic nervous system controls and regulates numerous bodilyfunctions including heart rate, respiration, digestion, urination,sexual response and others and consists of two major divisions, thesympathetic nervous system and the parasympathetic nervous system, shownin FIG. 11. Activation of the sympathetic nervous system results inpreparation of the body for stressful or emergency situations, whileactivation of the parasympathetic nervous system results in conservationand restoration and controls body processes during normal situations.

The present teaching, including our wearable tsDCS device, by modulatingspinal circuits at relevant spinal levels, can either activate orinhibit various parts of the sympathetic nervous system or theparasympathetic nervous system. There are myriad functions to beregulated in such a manner, and there are specific disorders related todysfunction of either the sympathetic or parasympathetic system. Normalfunctions to be regulated by a tsDCS device of these teachings thatmodulate sympathetic or parasympathetic activity include modulatingbronchodilation in the airways, modulating vasoconstriction in the skinand organs, stimulating gluconeogenesis and glucose release from theliver, stimulating secretion of epinephrine and norepinephrine by theadrenal gland, modulation of sweating, slowing or increasing heart rate,modulating tidal volume and rate of respiration, slowing or increasingintestinal processes involved with digestion, modulating urineproduction, modulating bladder contraction, modulating sphinctercontrol, stimulating erection and sexual arousal, and others. Table 5shows spinal levels of sympathetic outflow for various organs.

Beyond modulating normal functions, there are numerous disorders of theANS that have been described and are referred to as dysautonomias, andcan be due to failure or disruption of either the sympathetic orparasympathetic divisions of the ANS. Specific such disorders includeautoimmune autonomic ganglionopathy, congenital central hypoventilationsyndrome, familiar dysautonomia, Holmes-Adie syndrome, multiple systematrophy, Shy-Drager syndrome, neurally mediated syncope, orthostatichypotension, postural tachycardia syndrome, striatonigral degeneration,vasovagal syncope and others. By modulating spinal circuits, our tsDCSdevices treat autonomic disorders that currently have no effectivetreatments.

The above described tsDCS teaching, especially including a wearabledevice, enables convenient and constant wearable stimulation forpatients and individuals. In some embodiments, tsDCS is paired withstimulation of a peripheral nerve to an effector organ (e.g., muscle).Applications include modulating muscle tone in skeletal muscle, withsurface or implantable electrodes. Implantable electrodes and animplantable tsDCS stimulator embodiment of these teachings enablestimulation of smooth muscle such as that of bladder and bladdersphincters, anal sphincters, visceral organs, airways, heart, digestiveorgans, glands and other.

The processes and disorders of the ANS listed above can in someinstances be modulated more efficiently via an implanted electrode. Theimplanted electrodes preferably are at the nerve leading to the smoothmuscle, striated muscle or at a ganglion or plexus associated with theANS. This location can be directly at the sympathetic trunk or ganglia,celiac ganglion, superior mesenteric ganglion, inferior mesentericganglion, or by applying stimulation at the post-ganglionic nerve. Theparasympathetic nervous system has ganglia in close proximity to orlocated in the organs being innervated, and implantable electrodes canbe placed in proximity to these parasympathetic ganglia.

In one embodiment of these teachings, we provide a wearable orimplantable system for modulating sacral nerves. Referring to FIG. 14,regulating device 10 is provided as a wearable or implantable regulatingdevice 50, having the tsDCS-pDCS stimulation circuit 11 in a housing H.This would be for use with implantable electrode leads used forstimulation in practice of embodiments of these teachings. This may alsoinclude use as an implantable DC stimulator. In practice of theseteachings, we can treat flaccid, spastic or rigid conditions by use ofan implantable electrode for deep nerves to resolve a need foron-demand, frequent or continuous stimulation.

An illustrative use is shown in FIG. 14 for treating incontinence, suchas fecal or urinary, as muscle tone abnormalities. The muscle of thebladder can suffer either from excessive muscle tone or low muscle tone.In either case, a table top, wearable or implantable stimulator of theseteachings can be used to up or down regulate that muscle tone. In caseof a rigid or spastic bladder problem, the anode would be implanted overthe epidural surface of the sacral segments of the spinal cord and animplantable electrode cathode 27* would be implanted over the sacralnerves at the level of S2 to 84 as shown. For low muscle tone (flaccidbladder) the reverse polarities would be used. Device 100 is alsoprovided with a microprocessor with memory 91 in FIG. 9, which enablespre-programmed operation, or responsive remote operation via acommunication link 99. Controller circuit 90 monitors the DC source anddepending upon direction of the current establishes either anodal-spinaldown-regulate mode or the opposite up-regulate mode, and illuminateseither a down-regulate indicator 96 or an up-regulate indicator 98 forthe reverse, for further assuring safe operation of system 100.

This configuration may be used for urinary control as shown or for fecalcontrol when applied to control the anal sphincter. This configurationmay also be used for any other muscle problem that requires specificmuscle tone control. Embodiments of these teachings thus enabletreatment of humans using a wearable or implantable stimulation system.

Illustrative embodiments of the present teachings are discussed below byway of illustration and are not a limitation of the teachings. This isillustrated with neuromodulation applied to the autonomic nervous systemusing spinal tsDCS, demonstrating modulation of function by controlledexcitation and/or inhibition of neural pathways for treatment of variousneurological conditions. This may be accomplished with various devicesof the invention, including implantable or wearable devices and/orelectrodes.

Modulation of Renal Function

The kidney is responsible for excretion of the products of metabolismand removal of excess water, also having endocrine functions byproducing erythropoietin, renin and other factors. Neural control ofkidney and adrenal gland is shown in FIG. 15. Sympathetic control is bysympathetic efferents from T10-L1 that run via the sympathetic trunk andthe splanchnic nerves to the celiac ganglion and aortiocorenal ganglion.Post-ganglionic fibers contribute to the renal plexus which gives riseto the renal nerves that supply the kidney and its blood vessels,glomeruli and tubules. Stimulation of the renal nerves leads toincreased vasoconstriction of the blood vessels supplying the kidney,decreased removal of water and sodium from the blood, and increasedrenin secretion. Parasympathetic control is from the vagus nerve, whicharises from the dorsal motor nucleus of the vagus nerve in thebrainstem.

Role in Disease

Poor renal function leads to increased retention of metabolites andwater. Toxic metabolites can accumulate, and excess water can lead tohypertension (HTN), congestive heart failure (CHF), obesity and otherdisorders.

Neuromodulation strategies based on tsDCS to treat renal dysfunction

Decrease sympathetic tone—A decrease in sympathetic tone results indecreased retention of water and sodium. In an embodiment of the presentteachings, this is achieved by applying anodal tsDCS with cathodal andanodal electrodes applied at the spinal level of T10-L1 as shown in FIG.15. In a further embodiment, this is augmented with electricalinhibition of the renal nerves using implanted neural electrodes, and inone embodiment further including respective cathodal and anodal neuralelectrodes applied as shown in FIG. 15. Such an approach can be used totreat HTN, CHF, obesity and other disorders.

Increase parasympathetic tone—An increase in parasympathetic toneresults in decreased retention of water and sodium. To achieve this inpractice of an embodiment of these teachings, cathodal tsDCS is appliedat the level of the dorsal motor nucleus of the vagus nerve in thebrainstem and electrical stimulation is applied to the pre-ganglionicfibers of the vagus nerve using implanted electrodes, as shown in FIG.13. Cathodal tsDC to the vagal nucleus in this embodiment is appliedwith electrodes at T1-T2 and at the cranial apex. Alternatively in thisembodiment, cathodal tsDCS to the vagal nucleus is applied withelectrodes applied bilaterally to the mastoid processes of the skull.Such an approach could be used to treat HTN, CHF, obesity and otherdiseases.

Increase sympathetic tone—An increase in sympathetic tone results inincreased retention of water and sodium. In an embodiment of the presentteachings, this is achieved by cathodal tsDCS with cathodal and anodalelectrodes applied at the spinal level of T10-L1 as shown in FIG. 16. Ina further embodiment, this is augmented with electrical stimulation ofthe renal nerves using implanted neural electrodes, and in oneembodiment further including respective cathodal and anodal neuralelectrodes applied as shown in FIG. 16.

Modulation of Bladder Function

The bladder functions as a reservoir and is responsible for storingurine that has been formed by the kidneys in the process of eliminatingmetabolites and excess water from the blood. The stored urine isreleased via the urethra in the process of micturition. Referring toFIG. 17, sympathetic control is from sympathetic efferents from T11-L2that run via the sympathetic trunk and the splanchnic nerves to theinferior mesenteric ganglion. Post-ganglionic fibers contribute to thehypogastric plexus and reach the bladder where they synapse on thedetrusor muscle, and also synapse on the sphincter vesicae at thebladder neck. Parasympathetic control is from parasympathetic fibersthat arise from S2-S4 and travel via the pelvic splanchnic nerves tosynapse on post-ganglionic neurons located in a dense plexus among thedetrusor smooth muscle cells in the wall of the bladder. Post-ganglionicparasympathetic fibers cause contraction of the bladder detrusor muscleand relaxation of the sphincter vesicae. The external urethral sphincter(EUS) consists of striated muscle and is under voluntary control viaalpha motor neurons in Onuf's nucleus in the ventral horns of S2-S4.Afferent responses from bladder stretch receptors enter the spinal cordat T11-L2 and also S2-S4 where they travel up to brainstem areas.Sensory fibers in the urethral wall respond to urinary flow by causingfiring of their cell bodies located in dorsal root ganglia, whichsynapse on neurons in the spinal cord dorsal horn. These sensory fiberstravel to the spinal cord via the pudendal nerve, and transection ofthis sensory nerve reduces bladder contraction strength and voidingefficiency.

Role in Disease

Urinary retention is an inability to empty the bladder completely andcan be acute or chronic. Retention can be due to numerous issues,including constipation, prostatic enlargement, urethral strictures,urinary tract stones, tumors, and nerve conduction problems. Such nerveconduction problems are seen in brain and spinal cord injuries,diabetes, multiple sclerosis, stroke, pelvic surgery, heavy metalpoisoning, aging and idiopathically. These result in either weak bladdercontraction and/or excess sphincter activation. As such, modulationstrategies that enable improved emptying of the bladder are oftherapeutic interest.

Urinary incontinence is loss of bladder control leading to mild leakingall the way up to uncontrollable wetting. It results from weak sphinctermuscles, overactive bladder muscles, damage to nerves that control thebladder from diseases such as multiple sclerosis and Parkinson'sdisease, and can occur after prostate surgery. As such, modulationstrategies that treat urinary incontinence are of therapeutic interest.

Neuromodulation Strategies Based on tsDCS to Treat Urinary Retention

Increase parasympathetic tone—An increase in parasympathetic toneresults in increased bladder contraction and relaxation of the sphinctervesicae. In an embodiment of the present teachings, this is achieved byapplying cathodal tsDCS with cathodal and anodal electrodes applied atthe spinal level of S2-S4 as shown in FIG. 17. In a further embodiment,this is augmented with electrical excitation of the parasympatheticpreganglionic fibers in pelvic nerve using implanted neural electrodes,and in one embodiment further including respective cathodal and anodalneural electrodes applied as shown in FIG. 17.

Inhibit somatic efferents—Excessive activity in the somatic efferentsinnervating the striated muscle of the EUS results in contraction of thesphincter. In an embodiment of the present teachings, this is achievedby applying anodal tsDCS with cathodal and anodal electrodes applied atthe spinal level of S2-S4 as shown in FIG. 18. In a further embodiment,this is augmented with electrical inhibition of the pudendal nerve usingimplanted neural electrodes, and in one embodiment further includingrespective cathodal and anodal neural electrodes applied as shown inFIG. 18.

Stimulate sensory afferents—Stimulation of the sensory afferents thatfire in response to urine flow through urethra results in increasedstrength of bladder contraction and voiding efficiency. In an embodimentof the present teachings, this is achieved by applying cathodal tsDCSwith cathodal and anodal electrodes applied at the spinal level of S2-S4as shown in FIG. 19. In a further embodiment, this is augmented withelectrical excitation of the pudendal nerve using implanted neuralelectrodes, and in one embodiment further including respective cathodaland anodal neural electrodes applied as shown in FIG. 19.

Neuromodulation strategies based on tsDCS to treat urinary incontinence

Decrease parasympathetic tone—A decrease in parasympathetic tone wouldresult in relaxation of bladder contraction and contraction of thesphincter vesicae. In an embodiment of the present teachings, this isachieved by applying anodal tsDCS with cathodal and anodal electrodesapplied at the spinal level of S2-S4 as shown in FIG. 20. In a furtherembodiment, this is augmented with electrical inhibition of theparasympathetic preganglionic fibers in pelvic splanchnic nerves usingimplanted electrodes, and in one embodiment further including respectivecathodal and anodal neural electrodes applied as shown in FIG. 20.

Stimulate somatic efferents—Insufficient activation of the somaticefferents innervating the striated muscle of the EUS results in weakcontraction of this sphincter muscle. In an embodiment of the presentteachings, this is achieved by applying cathodal tsDCS with cathodal andanodal electrodes applied at the spinal level of S2-S4 as shown in FIG.21. In a further embodiment, this is augmented with electricalexcitation of the pudendal nerve using implanted electrodes, and in oneembodiment further including respective cathodal and anodal neuralelectrodes applied as shown in FIG. 21.

Modulation of Gastrointestinal System Function

The gastrointestinal (GI) system is responsible for digesting our food.The GI system is a series of hollow organs joined in a long tube goingfrom mouth to anus, and includes the esophagus, stomach, smallintestines, large intestines and rectum. The liver, pancreas andgallbladder are solid organs of the digestive system. Proper functioningof these hollow organs, together with the enzymes and molecules producedby these solid organs, and the collection of microrganisms colonizingthe GI system referred to as the microbiome, is critical for processing,digestion and elimination of foodstuffs. Sympathetic control of thestomach, small intestines and large intestines is by sympatheticefferents from T6-L2 that traverse the sympathetic trunk and thesplanchnic nerves (greater, lesser, least and lumbar splanchnics) toreach a network of three ganglia. These ganglia are the celiac ganglion,superior mesenteric ganglion (SMG) and the inferior mesenteric ganglion(IMG), which contain the cell bodies of post-ganglionic sympatheticneurons. Post-ganglionic fibers emerging from the celiac ganglioninnervate smooth muscle and glands of the stomach and small intestines,fibers from the SMG innervate distal portions of small intestines, andthe ascending and transverse colon, and fibers from the IMG traverse thehypogastric plexus to innervate the transverse colon, descending colonand rectum. Stimulation of the sympathetic nerves to the GI systemresults in inhibition of peristalsis, contraction of sphincters, andinhibition of secretions from glands. Parasympathetic control of thestomach, small intestines, ascending colon and transverse colon is fromthe vagus nerve, while parasympathetic control of the distal transversecolon, descending colon and rectum is from S2-S4. Cell bodies ofparasympathetic neurons located in the ventral horns of S2-S4 sendfibers through the pelvic nerves to post-ganglionic neurons located inAuerbach's (myenteric) and Meissner's (submucosal) plexuses. Thesepost-ganglionic neurons synapse on the smooth muscle and glands of thegastrointestinal tract they innervate. Stimulation of theparasympathetic system results in peristalsis, secretion from glands,and relaxation of sphincters, leading to increased GI motility.

Role in Disease

GI motility disorders are due to either decreased or increased motility,a term used to describe the contraction of the muscles that mix andpropel contents in the GI tract. These include disorders such as chronicintestinal pseudo-obstruction, irritable bowel syndrome, constipation,gastroesophageal reflux disease, dumping syndrome, intestinaldysmotility, diabetic gastroparesis, Hirschsprung's disease,gastroparesis, achalasia, small bowel bacterial overgrowth, diarrhea,functional heartburn, functional dysphagia, functional dyspepsia,post-prandial distress syndrome, epigastric pain syndrome, aerophagia,functional vomiting, chronic idiopathic nausea, functional bloating,functional abdominal pain disorder, functional sphincter of Oddidisorder, and other functional disorders. Beyond motility disorders,inflammatory immune-mediated disorders such as Crohn's disease andulcerative colitis also have mechanisms that are responsive to autonomiccontrol.

Neuromodulation Strategies Based on tsDCS to Increase GI Motility

Decrease sympathetic tone—A decrease in sympathetic tone results inincreased peristalsis and secretion. In an embodiment of the presentteachings, increased motility is achieved by applying anodal tsDCS withcathodal and anodal electrodes applied at the spinal level of T6-L2 asshown in FIG. 22. In a further embodiment, this is augmented withelectrical inhibition of the post-ganglionic nerve fibers distal to theceliac ganglion, SMG and IMG, using implanted electrodes, and in oneembodiment further including respective cathodal and anodal neuralelectrodes applied as shown in FIG. 22.

Increase parasympathetic tone—An increase in parasympathetic toneresults in increased peristalsis and secretion. In an embodiment of thepresent teachings, increased motility is achieved by applying cathodaltsDCS with cathodal and anodal electrodes applied at the spinal level ofS2-S4 as shown in FIG. 23. In a further embodiment, this is augmentedwith electrical excitation of the pre-ganglionic pelvic nerves usingimplanted neural electrodes, and in one embodiment further includingrespective cathodal and anodal neural electrodes applied as shown inFIG. 23. This can be combined with stimulation of the parasympatheticsystem emanating from the vagus nerve and innervating the stomach, smallintestines, proximal large intestines and spleen, as well as thekidneys, liver and heart. To achieve this in practice of an embodimentof the present teachings, cathodal tsDCS is applied at the level of thedorsal motor nucleus of the vagus nerve in the brainstem and electricalstimulation is applied to the pre-ganglionic fibers of the vagus nerveusing implanted electrodes. Cathodal tsDC to the vagal nucleus in thisembodiment is applied with electrodes at T1-T2 and at the cranial apex.Alternatively in this embodiment, cathodal tsDCS to the vagal nucleus isapplied with electrodes applied bilaterally on the mastoid process.

Neuromodulation Strategies Based on tsDCS to Decrease GI Motility

Increase sympathetic tone—An increase in sympathetic tone results indecreased peristalsis and secretion. In an embodiment of the presentteachings, this decreased motility is achieved by applying cathodaltsDCS with cathodal and anodal electrodes applied at the spinal level ofT6-L2. In a further embodiment, this is augmented with electricalexcitation of the post-ganglionic nerve fibers in and distal to thehypogastric plexus using implanted neural electrodes, and in oneembodiment further including respective cathodal and anodal neuralelectrodes in practice of the invention.

Decrease parasympathetic tone—A decrease in parasympathetic tone resultsin diminished peristalsis and secretion. In an embodiment of the presentteachings, this decreased motility is achieved by applying anodal tsDCSwith cathodal and anodal electrodes applied at the spinal level ofS2-S4. In a further embodiment, this is augmented with electricalinhibition of the pre-ganglionic pelvic nerves using implanted neuralelectrodes, and in one embodiment further including respective cathodaland anodal neural electrodes in practice of these teachings.

Modulation of Anal Sphincter Function

The anal sphincters are responsible for maintaining control over rectalcontents. Sympathetic outflow is from L1-L2, with pre-ganglionic fiberstraversing the sympathetic chain and synapsing on post-ganglionicneurons in the IMG. Post-ganglionic sympathetic fibers run via thehypogastric nerve, hypogastric plexus and pelvic nerves to innervate theinternal anal sphincter (IAS). Sympathetic stimulation maintains IAScontraction. The internal anal sphincter receives parasympathetic supplyfrom S2-S4 outflow, and its contraction is inhibited by parasympatheticfiber stimulation. The striated sphincter muscles (external analsphincter and puborectalis muscle) are under voluntary control and areinnervated by somatic efferent fibers traveling in the pudendal nerve(S2-S4).

Role in Disease

Dysfunction of the anal sphincter leads to fecal incontinence, whichresults in leakage or inability to retain gas and/or solid feces. Itresults from weak or damaged sphincter muscles, and damage to nervesthat control the sphincters from disorders such as multiple sclerosis,Parkinson's disease, spinal cord injury, brain injury and stroke. Assuch, modulation strategies that treat fecal incontinence are ofsignificant therapeutic interest.

Neuromodulation Strategies Based on tsDCS to Treat Fecal Incontinence

Increase sympathetic tone—An increase in sympathetic tone results inincreased contraction of the IAS. In an embodiment of the presentteachings, increased IAS contraction is achieved by applying cathodaltsDCS with cathodal and anodal electrodes applied at the spinal level ofL1-L2 as shown in FIG. 24. In a further embodiment, this is augmentedwith electrical excitation is applied to the post-hypogastric plexuspelvic nerves using implanted neural electrodes, and in one embodimentfurther including respective cathodal and anodal neural electrodesapplied as shown in FIG. 24.

Decrease parasympathetic tone—A decrease in parasympathetic tone resultsin lesser relaxation of IAS, enabling the IAS to stay more contracted.This greater contraction of IAS is achieved in an embodiment of thepresent teachings by applying anodal tsDCS with cathodal and anodalelectrodes applied at the spinal level of S2-S4 as shown in FIG. 25. Ina further embodiment, this is augmented with electrical inhibition ofthe parasympathetic preganglionic fibers in pelvic splanchnic nervesapplied using implanted neural electrodes, and in one embodiment furtherincluding respective cathodal and anodal neural electrodes applied asshown in FIG. 25.

Stimulate somatic efferents—Insufficient activation of the somaticefferents innervating the striated muscle of the external sphincterresults in weak contraction of this sphincter muscle. To achieve greatercontraction of the external sphincter muscle in practice of anembodiment of the present teachings, cathodal tsDCS is applied at thelevel of S2-S4 with cathodal and anodal electrodes applied as shown inFIG. 26. In a further embodiment, this is augmented with electricalexcitation of the pudendal nerve applied using implanted neuralelectrodes, and in one embodiment further including respective cathodaland anodal neural electrodes applied as shown in FIG. 26.

It will be appreciated that embodiments of the present teachings featuretsDCS spinal stimulation. In many embodiments, this tsDCS stimulation isaugmented with a neural stimulation. In practices of these teachings,peripheral pDCS is continuous, non-varying, steady-state direct currentstimulation, while in other embodiments, stimulation of a peripheralnerve or autonomic nerve fiber associated with an effector organ mayinclude pulsed electrical stimulation, functional electricalstimulation, continuous DCS, pulsed DCS, or other alternating signals.The present teachings also may be practiced with wirelessmicrostimulators (see, for example, U.S. Pat. No. 5,193,539, AProgrammable Implantable Microstimulator SoC, IEEE TRANSACTIONS ONBIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 5, NO. 6, DECEMBER 2011, both ofwhich are incorporated by reference herein in their entirety and for allpurposes) with Wireless Telemetry, micro-coil magnetic stimulation (see,for example, Magnetic Stimulation of Subthalamic Nucleus Neurons using

Micro-coils for Deep Brain Stimulation, 6th Annual International IEEEEMBS Conference on Neural Engineering San Diego, Calif., 6-8 Nov. 2013,which is incorporated by reference here in a its entirety and for allpurposes) and the like.

In one embodiment of the present teachings, peripheral stimulation iscontinuous steady-state and non-varying. In another embodiment of theinvention, excitation or inhibition of a stimulated autonomic nervefiber depends on the frequency of the applied electrical stimulation. Inone illustrative but non-limiting practice of the invention, inhibitionof parasympathetic fibers is achieved with high-frequency electricalstimulation (greater than about 50-100 Hz), while excitation ofparasympathetic fibers is achieved with low-frequency electricalstimulation (less than about 50-100 Hz). Similarly, inhibition ofsympathetic fibers is achieved with high-frequency electricalstimulation (greater than about 50-100 Hz), while excitation ofsympathetic fibers is achieved with low-frequency electrical stimulation(less than about 50-100 Hz).

In yet another embodiment of the present teachings, a series ofimplanted electrode leads for stimulation of multiple nerves leading tomultiple organs is provided. For example, one useful constellation offunctions to modulate for a specific scenario includes increasing airwaybronchodilation, increasing adrenal gland production of adrenergichormones, and increasing hepatic glucose production and release inanticipation of an intense burst of physical activity. Brain signals tothe sympathetic nervous system traversing the spinal cord are amplifiedby the wearable tsDCS device, which may also stimulate multiple nervesinvolved in multiple functions. As such, a neuromodulatory approach tothe amplification of the “fight-or-flight” response is enabled.

In embodiments of the present teachings, the tsDCS device is fullyimplantable, with electrode leads from the device to dorsal spinallocation and ventral location tunneled subcutaneously. Electrode leadsfrom the tsDCS device which function for peripheral stimulation are alsotunneled subcutaneously with electrodes implanted on the appropriatenerves of the effector organ being modulated. In another embodiment, thetsDCS device remains external to the body and wearable, but haselectrode leads for peripheral stimulation that are either surfacemounted or implanted.

In another embodiment of the present teachings, a wearable tsDCS unitthat wirelessly controls an implanted stimulator is combined with asensor that detects a relevant physiological state to form a closed-loopsystem. The wearable tsDCS unit wirelessly communicates with the sensor,which could be either implanted or wearable, and activates tsDCS spinalstimulation and stimulation of an effector organ via the implantedstimulator, when it detects a relevant state. The sensor can beconfigured to detect blood pressure, heart rate, body temperature,respiration rate, skin turgor, skin conductivity, oxygenation state,bladder pressure, urine osmolarity, hemodynamic parameters, specificcardiac rhythms by EKG, urethral pressure, anal sphincter pressure,muscle contraction state by EMG, specific brain waves by EEG,electrolytes, specific proteins and signaling molecules in specifictissue compartments, blood glucose concentration, gastric pH,gastrointestinal motility sounds, environmental cues such as specificsights, sounds and signals, and other parameters depending on intendedapplication. The neuromodulation system is thus activated upon sensing aspecific state, and inactivated when that state no longer holds. In oneembodiment of the present teachings, the system also includes a sensorconfigured to detect a predetermined parameter, such as those listedherein above, and configured to provide a sensed value of thepredetermined parameter to the controller component. The controllercomponent is further configured to initiate stimulation, initiation ofstimulation determined by whether the sensed value is less than orexceeds a predetermined value denoting the specific state.

Another embodiment includes method and apparatus for neuromodulatoryregulation of effector organs by modulation of spinal neurons, havinganode and cathode sources, having a spinal circuit for biasing a spinalelectrode at a first polarity and biasing a distal reference electrodeat a second polarity, and having a neural circuit for biasing a nerveassociated with the muscle, the neural circuit having a charge-balancingelectrode device having a first and second neural electrodes forlimiting the polarizing effect of current flow in the nerve, the neuralcircuit biasing the first neural electrode to the second polarity andthe second neural electrode at the first polarity, wherein the spinalelectrode and the second neural electrode are connected to one of thesources and the first electrode is connected to the other of thesources, for activation of the effector organ of interest, as describedin embodiments above.

This disclosure includes description by way of example of a deviceconfigured to execute functions (hereinafter referred to as computingdevice) which may be used with the presently disclosed subject matter.The description of the various components of a computing device is notintended to represent any particular architecture or manner ofinterconnecting the components. Other systems that have fewer or morecomponents may also be used with the disclosed subject matter. Acommunication device may constitute a form of a computing device and mayat least include a computing device. The computing device may include aninter-connect (e.g., bus and system core logic), which can interconnectsuch components of a computing device to a data processing device, suchas a processor(s) or microprocessor(s), or other form of partly orcompletely programmable or pre-programmed device, e.g., hard wired andor application specific integrated circuit (“AS1C”) customized logiccircuitry, such as a controller or microcontroller, a digital signalprocessor, or any other form of device that can fetch instructions,operate on pre-loaded/pre-programmed instructions, and/or followedinstructions found in hardwired or customized circuitry to carry outlogic operations that, together, perform steps of and whole processesand functionalities as described in the present disclosure.

Each computer program may be implemented in any programming language,such as assembly language, machine language, a high-level proceduralprogramming language, or an object-oriented programming language. Theprogramming language may be a compiled or interpreted programminglanguage.

Each computer program may be implemented in a computer program producttangibly embodied in a computer-readable storage device for execution bya computer processor. Method steps of these teachings may be performedby a computer processor executing a program tangibly embodied on acomputer-readable medium to perform functions of these teachings byoperating on input and generating output.

In this description, various functions, functionalities and/oroperations may be described as being performed by or caused by softwareprogram code to simplify description. However, those skilled in the artwill recognize what is meant by such expressions is that the functionsresult from execution of the program code/instructions by a computingdevice as described above, e.g., including a processor, such as amicroprocessor, microcontroller, logic circuit or the like.Alternatively, or in combination, the functions and operations can beimplemented using special purpose circuitry, with or without softwareinstructions, such as using Application-Specific Integrated Circuit(AS1C) or Field-Programmable Gate Array (FPGA), which may beprogrammable, partly programmable or hard wired. The applicationspecific integrated circuit (“AS1C”) logic may be such as gate arrays orstandard cells, or the like, implementing customized logic bymetalization(s) interconnects of the base gate array AS1C architectureor selecting and providing metalization(s) interconnects betweenstandard cell functional blocks included in a manufacturer's library offunctional blocks, etc. Embodiments can thus be implemented usinghardwired circuitry without program software code/instructions, or incombination with circuitry using programmed software code/instructions.

Thus, the techniques are limited neither to any specific combination ofhardware circuitry and software, nor to any particular tangible sourcefor the instructions executed by the data processor(s) within thecomputing device. While some embodiments can be implemented in fullyfunctioning computers and computer systems, various embodiments arecapable of being distributed as a computing device including, e.g., avariety of forms and capable of being applied regardless of theparticular type of machine or tangible computer-readable media used toactually effect the performance of the functions and operations and/orthe distribution of the performance of the functions, functionalitiesand/or operations.

The interconnect may connect the data processing device to define logiccircuitry including memory. The interconnect may be internal to the dataprocessing device, such as coupling a microprocessor to on-board cachememory or external (to the microprocessor) memory such as main memory,or a disk drive or external to the computing device, such as a remotememory, a disc farm or other mass storage device, etc. Commerciallyavailable microprocessors, one or more of which could be a computingdevice or part of a computing device, include a PA-RISC seriesmicroprocessor from Hewlett-Packard Company, an 80×86 or Pentium seriesmicroprocessor from Intel Corporation, a PowerPC microprocessor fromIBM, a Spare microprocessor from Sun Microsystems, Inc, or a 68xxxseries microprocessor from Motorola Corporation as examples.

The inter-connect in addition to interconnecting such asmicroprocessor(s) and memory may also interconnect such elements to adisplay controller and display device, and/or to other peripheraldevices such as input/output (I/O) devices, e.g., through aninput/output controller(s). Typical I/O devices can include a mouse, akeyboard(s), a modem(s), a network interface(s), printers, scanners,video cameras and other devices which are well known in the art. Theinter-connect may include one or more buses connected to one anotherthrough various bridges, controllers and/or adapters. In one embodimentthe I/O controller includes a USB (Universal Serial Bus) adapter forcontrolling USB peripherals, and/or an IEEE-1394 bus adapter forcontrolling IEEE-1394 peripherals.

The memory may include any tangible computer-readable media, which mayinclude but are not limited to recordable and non-recordable type mediasuch as volatile and non-volatile memory devices, such as volatile RAM(Random Access Memory), typically implemented as dynamic RAM (DRAM)which requires power continually in order to refresh or maintain thedata in the memory, and non-volatile RAM (Read Only Memory), and othertypes of non-volatile memory, such as a hard drive, flash memory,detachable memory stick, etc. Non-volatile memory typically may includea magnetic hard drive, a magnetic optical drive, or an optical drive(e.g., a DVD RAM, a CD RAM, a DVD or a CD), or other type of memorysystem which maintains data even after power is removed from the system.

For the purposes of describing and defining the present teachings, it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that may be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation may vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

While these teachings have been described in terms of specificembodiments, it is evident in view of the foregoing description thatnumerous alternatives, modifications and variations will be apparent tothose skilled in the art. Accordingly, these teachings are intended toencompass all such alternatives, modifications and variations which fallwithin the scope and spirit of the present teachings and the followingclaims.

The invention claimed is:
 1. A system for regulation of an effectororgan in a vertebrate being, the system comprising: a first stimulationcomponent configured to provide peripheral direct current stimulation ofa peripheral nerve associated with activity of a target effector organof a vertebrate being; said first stimulation component including aneural stimulation circuit having neural stimulation poles configured tostimulate said peripheral nerve; a second stimulation componentconfigured to provide spinal direct current stimulation at a spinallocation associated with regulation of said activity of said targeteffector organ, said second stimulation component defining a spinalstimulation circuit having an active spinal stimulation pole and aspinal reference pole, said spinal stimulation circuit configured toprovide constant-current trans-spinal direct current stimulation betweensaid spinal stimulation pole and said spinal reference pole forstimulating said spinal location; the active spinal stimulation polebeing relatively proximal to said spinal location; the spinal referencepole being relatively distal to said spinal location; and a controllercomponent configured to ensure that said active spinal pole and saidproximal neural pole are excited at opposite polarities, forming aresulting polarization circuit, said resulting polarization circuitbeing configured to provide a polarizing current flow between saidactive spinal pole and said proximal neural pole according to saidopposite polarities, for regulating said activity of said targeteffector organ according to said polarizing current flow.
 2. The systemof claim 1 wherein at least one of said first and second stimulationcomponents is configured to provide non-varying constant direct currentelectrical stimulation.
 3. The system of claim 1 wherein said controllercomponent is further configured to simultaneously control the range ofcurrent supplied by the first and second stimulation components.
 4. Thesystem of claim 3 wherein said first stimulation component includespositive and negative poles for providing stimulation current tostimulation electrodes disposed for stimulation of said nerve associatedwith said target effector organ, said positive and negative polesdisposed for one electrode operatively connected to the positive poleand another electrode operatively connected to the negative pole.
 5. Thesystem of claim 4 wherein said first stimulation component includespositive and negative poles for providing stimulation current tostimulation electrodes disposed for delivering stimulation across saidspinal location, a first of said stimulation electrodes providingpositive stimulation of said spinal location.
 6. The system of claim 5wherein at least one of said stimulation electrodes is implanted.
 7. Thesystem of claim 1 wherein at least one of the controller component andan electrical source are disposed in a wearable housing.
 8. The systemof claim 1 wherein at least one of said first and second stimulationcomponents is configured to provide pulsed direct current stimulation.9. The system of claim 1 wherein the target effector organ is aneffector organ innervated by an autonomic nervous system, wherein thespinal direct current stimulation is provided to a spinal locationassociated with efferent neural outflow to the autonomic nervous system.10. The system of claim 1 further comprising a sensor configured todetect a predetermined parameter and configured to provide a sensedvalue of the predetermined parameter to the controller component, andwherein the controller component is further configured to initiatestimulation, said initiation determined by whether the sensed valueexceeds or is less than a predetermined value.
 11. The system of claim 5wherein said controller is configured to associate said positive polewith said spinal location via an electrode associated with said activespinal stimulation pole and to associate said negative pole with aspinal reference electrode of said spinal stimulation circuit.
 12. Thesystem of claim 1 wherein said direct current for spinal stimulationranges from about 2 mA to about 4 or 5 mA.
 13. The system of claim 1further including a housing, wherein said housing is configured formounting said second stimulation component on said spinal location incontact with an electrode coupled to said active spinal stimulationpole.
 14. The system of claim 13 wherein said housing is furtherconfigured to provide connection to said spinal reference pole of saidspinal stimulation circuit.
 15. The system of claim 14 wherein saidresulting polarization circuit provides neural control to any one of thegroup of systems of the being consisting of urinary, fecal,gastrointestinal, respiratory, or cardiac systems and wherein saidspinal direct current stimulation is provided to a spinal locationassociated with efferent neural outflow to one of said urinary, fecal,renal, gastrointestinal, respiratory, or cardiac systems.
 16. The systemof claim 15 wherein said target effector organ is a sphincter muscle.17. The system of claim 1 wherein said regulation is associated with atleast one activity of one of the set of activities consisting of:modulating bronchodilation in the airways of the being, modulatingvasoconstriction in the skin and organs of the being, stimulatinggluconeogenesis and glucose release from the liver of the being,stimulating secretion of epinephrine and norepinephrine by the adrenalgland of the being, modulation of sweating of the being, slowing andincreasing heart rate of the being, modulating tidal volume and rate ofrespiration of the being, slowing and increasing intestinal processesinvolved with digestion of the being, modulating urine production of thebeing, modulating bladder contraction of the being, modulating sphinctercontrol of the being, stimulating erection and sexual arousal of thebeing, and for stimulating smooth muscle of the being, including bladdersphincters, anal sphincters, visceral organs, airways, heart, digestiveorgans, and glands.
 18. The system of claim 1 wherein said firststimulation component includes a first electrical source and said secondstimulation component includes a second electrical source.
 19. Thesystem of claim 18 wherein the first electrical source and the secondelectrical source are a same electrical source; and wherein the sameelectrical source is configured for producing non-varying directcurrent.
 20. The system of claim 19 wherein said non-varying directcurrent for spinal stimulation ranges from about 2 mA to about 4 or 5mA.
 21. The system of claim 18 wherein the first electrical source isimplanted; and wherein the controller component is operatively connectedto the first electrical source by a wireless connection.